Autoimmune diseases are serious diseases, which cause significant health and personal problems and currently represent the fourth most important health problem in industrialised countries. As an example, Multiple Sclerosis (MS) is an autoimmune disease with great healthcare relevance that causes significant sequelae. Similarly, transplant rejection, a specific case of autoimmunity in which the activation of transplant antigen-specific T lymphocytes leads to their elimination, represents a serious complication for those patients receiving transplants, with a high personal and social cost.
Due to their particular characteristics (mechanisms and response to treatments), autoimmune diseases form a specific sub-group within inflammatory diseases. As is well-known, inflammatory diseases are those in which innate inflammation predominates or in which the treatment is designed to fight the innate inflammation. However, autoimmune diseases are different from inflammatory diseases in that inflammation by adaptive immunity (lymphocytes) predominates; consequently, classical anti-inflammatory treatments, aimed at modulating the innate inflammation, are not effective in the treatment of autoimmune diseases, seemingly due to the fact that, in order to control the chronic activity of an autoimmune disease it is necessary, in addition to suppressing the local inflammation, to modulate lymphocyte activity by means of immunomodulators.
The treatment of autoimmune diseases is a serious problem, since many therapies are symptomatic and those therapies which modify the course of the disease have partial effectiveness and side-effects, as well as significant costs. The control of autoimmune diseases is based, in general, on the modulation of T lymphocyte activation by means of immunosuppressant or immunomodulatory therapies; for this reason, the classical anti-inflammatory therapies are ineffective.
Currently, in treating autoimmune diseases and transplant rejection, three types of therapies tend to be used, all of them centred on limiting the activation and effect of autoreactive T lymphocytes:                a) on the one hand, the administration of corticoids (e.g. prednisone, 5′-methylprednisone, dexamethasone and ACTH, amongst others), either orally, subcutaneously or intravenously and in the form of boluses, for short periods of time or indefinitely, may alleviate some of these diseases, albeit always in a partial manner and with significant long-term secondary effects which limit their use;        b) on the other hand, the administration of immunosuppressants (e.g. cyclophosphamide, mitoxantrone, methrotrexate, azathioprine and cyclosporin A, amongst others), orally or intravenously, improves the control of many of these diseases, albeit with potentially serious or even lethal side-effects, which greatly limit their use; and        c) on the other hand, the administration of immunomodulators (e.g. interferon-beta, interferon-alpha, glatiramer acetate, anti-CD20 or anti-TNFa monoclonal antibodies, amongst others) improves the control of these diseases, albeit in a partial manner, with habitual side-effects and with a high cost since they are biotechnological products.        
Therefore, it would of great interest to have a new treatment available that is effective in preventing lymphocyte activation and that prevents or reduces the activity of autoimmune diseases and transplant rejection, with limited secondary effects.
It has now been found that 5′-methylthioadenosine (MTA) may be used in the prevention and/or treatment of autoimmune diseases, as well as in the prevention and/or treatment of transplant rejection and, specifically, in the prevention and/or treatment of Multiple Sclerosis (MS).
MTA is a hydrophobic adenine sulphur-nucleoside, in which the hydroxyl group in the 5′ position of the ribose is replaced by a methylthio group. MTA is found in low proportions in all cellular types, including prokaryotes, yeasts, plants and higher eukaryotes, and it has been observed that it is naturally present in all mammal tissues. MTA is a well-known molecule that has very diverse properties for cancer control, as well as for regeneration and innate inflammation.
U.S. Pat. No. 4,454,122 discloses the use of MTA as an anti-inflammatory, analgesic and anti-pyretic agent; specifically, the use of MTA in the treatment of innate inflammation. The anti-inflammatory activity is analysed by means of the suppression of the innate immune response in edema, pleuritis and foreign-body granuloma models. The role of MTA in the suppression of lymphocyte activation is not analysed, nor is its role as an immunomodulator in autoimmune diseases or transplant rejection.
The effects of MTA on cancer have also been studied. It has been extensively observed that MTAP (5′-methylthioadenosine phosphorylase) activity is lacking in many malignant cells, and that, in culture, these MTAP-deficient cells secrete MTA instead of metabolising it. As an example, international patent application WO2004/074325 discloses the use of compounds which inhibit the MTAP enzyme in cancer treatment. In experimental models of chemically-induced hepatocarcinogenesis, in which it has been observed that MTA levels are reduced, the administration of MTA induces a dose-dependent inhibition of liver pre-neoplastic lesions and DNA synthesis.
On the other hand, the function and proliferation of T lymphocytes seems to be particularly sensitive to inhibition by MTA. This compound inhibits, in a reversible, non-toxic and dose-dependent manner, the proliferation of mitogen-stimulated murine lymphoid cell lines and human peripheral lymphocytes. Amongst the MTA effects which may interfere with cell proliferation, one can cite the inhibition of protein methylation or the inhibition of phosphodiesterase activity. The authors of the invention themselves proclaimed, in a conference paper titled “A Methylation-Inhibitor Suppresses T Cell Activation and Prevents Experimental Autoimmune Encephalomyelitis”, in the 7th Meeting of the International Society of Neuroimmunology, Venice, September 2004 [Abstract published in the Journal of Neuroimmunology 2004, Vol. 154, numbers 1-2, page 85], the utility of MTA as a potent inhibitor of methylation reactions, which prevents the development of an autoimmune response in an animal model of Experimental Autoimmune Encephalomyelitis (EAE), consisting of Lewis rats immunised with myelin basic protein (MBP).